The impact of immunosuppressive medications

Patients with rheumatoid arthritis (RA) have an increased risk of heart attack and stroke. As per extensive evidence, the key driver for this increased risk of cardiovascular disease is the increased systemic inflammation characteristic of RA. Studies are less clear on whether medications that work to reduce RA's inflammatory symptoms provide protective benefits against cardiovascular events. Some data have suggested that the most potential biologic therapies, such as the TNF blockers, might reduce the risk of ischemic cardiovascular events.

To investigate, scientists at Harvard Medical School's Brigham and Women's Hospital compared the effects of a variety of immunosuppressive agents on cardiovascular events in a large sample of RA patients. Based on their findings, featured in the December 2006 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), TNF blockers were not linked to either a reduction or an increase in the risk of heart attack or stroke compared with the most usually used RA therapy, methotrexate. While certain anti-inflammatory drugs appeared to exacerbate the risk of heart attack and stroke for RA patients, especially among older women.

Drawing on a database of Medicare patients receiving a drug benefit from the state of Pennsylvania, the scientists identified 946 individuals who had been diagnosed with RA, prescribed an immunosuppressive agent, and hospitalized for either heart attack or stroke within a six-year period. These patients were defined as case subjects for studying the role of anti-inflammatory RA therapies in the risk of cardiovascular disease. Each case subject was matched by age and gender to ten controls. The controls, a total of 9,460 RA patients, did not experience cardiovascular events during the delineated period. All the subjects were over age 65 and most were female and white.

Current treatment was defined by having a prescription filled 90 days previous to the date of the case subject's first cardiovascular event. Scientists then categorized the different drugs and analyzed their relationship to heart attack and stroke using standard risk regression models. Methotrexate (MTX) was considered individually and, as the most widely prescribed immunosuppressive agent, used as the reference group for other therapies.

Compared with MTX, scientists found neither a protective nor detrimental cardiovascular impact for biologic agents, including the interleukin-1 receptor antagonist anakinra as well as the three TNF blockers, adalimumab, etanercept, and infliximab. Oral glucocorticoids, steroid hormones like prednisone, were linked to a 50 percent increase in the probability of a cardiovascular event when taken alone; a similar trend in the direction of risk was seen with glucocorticoids combination treatment. Most significantly, cytotoxic agents, also known as disease-modifying antirheumatic drugs (DMARDs), were found to increase the likelihood of heart attack or stroke by 80 percent when used without other drugs. This finding applied to azathioprine, cyclosporine, and leflunomide.

Daniel Solomon, MD, MPH, the study's lead author and Associate Professor of Medicine at Brigham and Women's Hospital and Harvard Medical School, acknowledges that this study has several limitations. Given the data source--a huge healthcare utilization database--it was difficult to assess the severity of RA and the contribution of other cardiovascular risk factors, such as smoking and diet. Furthermore, the subjects were primarily elderly, with a mean age of 82, and in a frail state of health. "Experimental designs, such as randomized clinical trials, would be very useful to better understand the effects of these agents on cardiovascular outcomes among patients with RA," Dr. Solomon reflects.


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